KR0156948B1 - Isoindazole compound - Google Patents

Abstract

Isoidazole compound of the following general formula (1) or its salt; Its production method; And the pharmaceutical use of said compound chi salts thereof in particular as an angiotensin II antagonist and a prophylactic and therapeutic agent for circulatory diseases (especially hypertension and heart failure);

[Wherein Q is a heterocyclic derivative of the following general formula (2) or (3).]

(Wherein, the other symbols of the above general formula are as defined in the specification)

The compound and its salts show good angiotensin II antagonism and have low toxicity. That is, they are useful as angiotensin II antagonists for the treatment or prevention of angiotensin II intervening diseases such as hypertension (eg, essential hypertension, nephrotic hypertension) and heart failure.

Description

[Name of invention]

Isoindazole Compound

Detailed description of the invention

[Technical Field]

The present invention relates to novel isoindazole (ie 2H-indazole) compounds and salts thereof having good pharmacological action. More specifically, the present invention relates to novel isindazole compounds and salts thereof which have angiotensin II antagonism and are useful as agents for the prevention and treatment of circulatory diseases such as hypertension and heart failure.

[Background]

The blood pressure of the living body is regulated by the sympathetic nervous system and the balance between the booster and the tensometer. Very related to the booster is the Lenin-Angiotensin system. Lenin acts on angiotensinogen to produce angiotensin I. Angiotensin I is further converted to angiotensin II by an angiotensin converting enzyme. Angiotensin II not only has strong vasoconstrictive action, but also acts in the adrenal cortex to promote the release of aldosterone, thereby raising blood pressure. Since angiotensin II acts through the angiotensin II receptor on the cell membrane, its antagonist can be used as a therapeutic agent for hypertension caused by angiotensin II, just like an angiotensin converting enzyme inhibitor.

To date, peptidic angiotensin II antagonists represented by sararacin are known, but these are peptide preparations and therefore are not effective by oral administration. However, recent nonpeptidic angiotensin II antagonists have been reported (e.g., Japanese Patent Laid-Open Nos. 71074/1981, 501020/1991, 95181/1991, 236377/1991, 271288/199). . These have been found to be effective by oral administration.

Accordingly, it is an object of the present invention to provide nonpeptidic compounds which have good angiotensin II antagonism and are effective by oral administration.

[Initiation of invention]

The present inventors have made intensive studies to achieve the above object, and now it is a novel isoindazole (2H-indazole) compound of the following general formula (I) which has excellent angiotensin II antagonism and is effective by oral administration and its A salt was found.

That is, the present invention relates to novel isoindazole compounds of the following general formula (I) (hereinafter sometimes referred to as isoindazole compound (I)) and salts thereof.

[Wherein, Q is a heterocyclic derivative of the following general formula (2) or (3). :

In General Formulas (1), (2) and (3), R ¹ to R ⁸ , X, and Y represent the following.

R ¹ : lower alkyl group, halo-lower alkyl group, cyclo lower alkyl group, alkenyl group, alkoxyl group, alkoxyl-lower alkyl, or alkylthio group.

R ² and R ³ may be the same or different and each independently represent a hydrogen atom, a halogen atom, a lower alkyl group, a halo-lower alkali group, a cyclo-lower alkyl group, an alkenyl group, an alkoxyl group, -C _m F _{2m + 1} , -(CH ₂ ) _n R ⁹ , or-(CH ₂ ) _p COR ¹⁰ .

R ⁴ and R ⁵ , which may be the same or different, are each independently a hydrogen atom, a halogen atom, a lower alkyl group, an alkoxyl group, or —C _m F _{2m + 1} .

R ⁶ : carboxyl group, -COOR ¹¹ , -CONH ₂ , cyano group, -SO ₃ H, -SO ₂ NH ₂ , -NHSO ₂ CF ₃ , or a C-linked tetrazolyl group.

R ⁷ and R ⁸ may be the same or different and are each independently a hydrogen atom, a halogen atom, a lower alkyl group, an alkoxyl group or -C _m F _{2m + 1} .

X and Y may be the same or different, and are each independently CH or a nitrogen atom.

In the above definitions, R ⁹ to R ¹¹ , m, n and p represent the following.

R ⁹ : hydroxyl group or alkoxyl group

R ^{10 is a} hydrogen atom. Hydroxyl group, lower alkyl group, or alkoxyl group

R ¹¹ : lower alkyl group, alkenyl group, cyclo-lower alkyl group, aryl group or aralkyl group

m: integer of 1-6

n is an integer of 1 to 4

p is an integer of 0 to 4]

The present invention also relates to a process for the preparation of isoindazole compound (1) and salts thereof, wherein the compound of formula (4) is reacted with a compound of formula (5) or (6):

[Wherein L is a leaving group and R ²⁴ , R ²⁵ , R ²⁶ , R ²⁷ and R ²⁸ are the same as the corresponding R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ of General Formula (1), respectively; , A group that can be converted to the corresponding R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ , respectively.]

[Wherein, R ²³ , R ²² and R ²³ are the same as the corresponding R ¹ , R ² and R ³ of the general formula (2), or can be converted into the corresponding R ¹ , R ² and R ³ , respectively to be.]

[Wherein R ²¹ , R ²² and R ²³ are each the same as corresponding R ¹ , R ² and R ^{3 in} formula (3), or can be converted to the corresponding R ¹ , R ² and R ³ , respectively There is a flag.]

The present invention also provides a pharmaceutical composition comprising the above isoindazole compound (1) or a salt thereof and a pharmaceutically acceptable carrier; Angiotensin II antagonist containing the said isoindazole compound (1) or its salt as an active ingredient; And a prophylactic and therapeutic agent for circulatory diseases (particularly hypertension and heart failure), which contain the isoidazole compound (1) or a salt thereof as an active ingredient.

Salts of isoindazole compound (1) include, for example, isoindazole compound (1) and acid addition salts derived from inorganic or organic acids. Examples of such salts include hydrochloride, hydrobromide, phosphate, phosphate, methanesulfonate, p-toluenesulfonate, oxalate, tartarate, citrate, maleate, fumarate, succinate, lactate, glutarate, Acetates, trifluoroacetates and various salts of amino acids.

Also included are salts formed from isoindazole compounds (1) and bases. The salts may include salts generated from alkali metals such as sodium and potassium and alkaline earth metals such as magnesium, and ammonium or substituted ammoniums such as dimethylammonium and triethylammonium.

In the present specification, the lower organic group means a group having 1 to 6 carbon atoms.

R^One-R⁵, R⁷, R⁸, And R¹¹Lower alkyl groups in can be linear or branched, and include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentel and hexyl groups.

The halo-lower alkyl group in R ¹ to R ³ is a lower alkyl group substituted by halogen (eg, fluorine, chlorine, blomiode) and may be straight or branched. Examples thereof include chloromethyl group, 2-chloroethyl group, bromomethyl group, 2-bromoethyl group, 1,2-dichloroethyl group, 1,2-dibromoethyl group and 3-trifluoromethylpropyl group.

The cyclo-lower alkyl group in R ¹ to R ³ and R ¹¹ is a C 3 to C 6 cycloalkyl group constituting the ring, and includes a cyclopropyl group, a cyclobutyl group, a cyclopentyl group and a cyclohexyl group.

The alkenyl groups in R ¹ to R ³ and R ¹¹ are preferably lower alkenyl and more preferably lower alkenyl groups having 2 to 4 carbon atoms. It may be linear or branched, and includes vinyl group, allyl group, 1-propenyl group, isopropenyl group and 1-butenyl group.

The alkoxyl groups in R ¹ to R ⁵ and R ⁷ to R ¹⁰ are preferably lower alkoxyl groups, and more preferably lower alkoxyl groups having 1 to 4 carbon atoms. It may be straight or branched and includes methoxy, ethoxy, propoxy and butoxy groups.

The alkoxyl-lower alkyl group in R ¹ may be straight or branched and its alkoxyl moiety is preferably a lower alkoxyl group. Examples thereof include methoxyethyl, 2-methoxypropyl and 2-ethoxyethyl.

The alkylthio group in R ¹ is preferably a lower alkylthio group, more preferably a lower alkylthio group having 1 to 4 carbon atoms. It may be linear or branched, and may include methylthio group, ethylthio group, propylthio group and butylthio group.

The halogen atom in R <^2> -R <^5> , R <^7> and R <^8> means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

The aryl group in R ¹¹ is a monovalent aromatic hydrocarbon group which may have a substituent such as a halogen, a lower alkoxy group or a lower alkylamino group, preferably a phenyl group or a derivative thereof. Examples thereof include alkoxyphenyl groups such as p-halophenyl groups such as phenyl group, tolyl group, p-chlorophenyl group and p-bromophenyl group, methoxyphenyl group and ethoxyphenyl group, dialkylamino groups such as dimethylaminophenyl group and diethylaminophenyl group. Phenyl group is included.

The aralkyl group in R ¹¹ is an alkyl group substituted with the aryl group exemplified above. The alkyl group preferably has 1 to 4 carbon atoms, and examples thereof include benzyl group, benzhydryl group, trityl group and phenethyl group.

The leaving group represented by L is, for example, a chlorine, bromine, iodine, methanesulfonyloxy group or p-toluenesulfonyloxy group.

Examples of the group of R ²¹ to R ²⁸ that can be converted into R ¹ to R ³ include the same groups as the R ¹ to R ³ , amino groups, protective amino groups, mercapto groups, and protecting groups, except that the functional groups are protected by a protecting group. Mercapto group is mentioned.

Although there are no particular restrictions on the positions of the substituents R ² to R ⁴ and R ⁶ to R ⁸ of the general formulas (1), (2) and (3), R ⁶ is preferably an ortho position relative to the bonding site. The same applies to the positions of substituents R ²² to R ²⁴ and R ²⁶ to R ^{28 in} the general formulas (4), (5) and (6).

Preferred isoindazole compound (1)

(1) Q is a heterocyclic derivative of formula (2), R ¹ is a lower alkyl or alkenyl group, R ² is a chlorine atom, R ³ is-(CH ₂ ) _n R ⁹ or-(CH ₂ ) _p COR ¹⁰ (wherein R ⁹ is a hydroxyl or alkoxyl group, R ¹⁰ is a hydrogen atom, a hydroxyl group or an alkoxyl group, n is an integer from 1 to 4 and p is an integer from 0 to 4) Compound of formula (1); And

(2) Q is a heterocyclic derivative of formula (3), R ¹ is a lower alkyl group or an alkenyl group, R ² and R ³ may be the same or different and each independently represent a hydrogen atom, a halogen atom, a lower alkyl group, -(CH ₂ ) _n R ⁹ or-(CH ₂ ) _p COR ¹⁰ (wherein R ⁹ is a hydroxyl group or an alkoxyl group, R ¹⁰ is a hydrogen atom, a hydroxyl group or an alkoxyl group, n is 1-4) P is an integer of 0 to 4), X is a nitrogen atom, Y is CH, R ⁴ is a hydrogen atom, R ⁵ is a hydrogen atom or a halogen atom, and R ⁶ is a carboxyl group or C- Compounds of the general formula (1) which are bonded tetrazolyl groups, R ⁷ and R ⁸ may be the same or different and each independently represent a hydrogen atom, a fluorine atom, a chlorine atom, a lower alkyl group or an alkoxyl group.

More preferred isoindazole compound (1)

(3) Q is a heterocyclic derivative of formula (2), R ¹ is a lower alkyl group, R ² is a chlorine atom, R ³ is-(CH ₂ ) _n R ⁹ or-(CH ₂ ) _p COR ¹⁰ (Wherein R ⁹ is a hydroxyl group, R ¹⁰ is a hydrogen atom, a hydroxyl group or an alkoxyl group, n is 1, p is 0 or 1), R ⁴ is a hydrogen atom, and R ⁵ is hydrogen An atom, a fluorine atom, a chlorine atom or a bromine atom, R ⁶ is a carboxyl group or a C-linked tetrazolyl group, and R ⁷ and R ⁸ may be the same or different and are each independently a hydrogen atom, a fluorine atom, a chlorine atom, a lower atom The compound of formula (1) which is an alkyl group; And

(4) Q is a heterocyclic derivative of formula (3), R ¹ is a lower alkyl group, R ² and R ³ may be the same or different and each independently represent a hydrogen atom, a lower alkyl group,-(CH ₂ ) _n R ⁹ or — (CH ₂ ) _p COR ¹⁰ (wherein R ⁹ is a hydroxyl group, R ¹⁰ is a hydrogen atom, a hydroxyl group or an alkoxy group, n is 1 and p is 0 or 1), R ⁴ is a hydrogen atom, R ⁵ is a hydrogen atom, a fluorine atom, a chlorine atom or a bromine atom, R ⁶ is a carboxyl group or a C-linked tetrazolyl group, and R ⁷ and R ⁸ may be the same or different and are each independently And hydrogen, fluorine, chlorine or lower alkyl group, X is nitrogen atom and Y is CH.

When Q in general formula (1) is represented by general formula (3), especially preferably, the total carbon number of the substituent with respect to R <^1> , R <^2> and R <^3> should be 4.

Isoindazole compound (1) is manufactured by the method illustrated below.

The method of claim 1 consists of the conversion of a compound of the general formula (1): Method (A). The second method consists of converting a similar compound (having a substituent different from the compound of general formula (1) but having the same skeleton, hereinafter used in the same sense) to a compound of general formula (1): Method (B) . The third method consists in synthesizing the compound of formula (1) or a analogous compound thereof through the reaction of two or more intermediate compounds: Method (C). The analogous compound obtained in (C) is converted into the compound of the general formula (1) by the method (B). This method (C) relates to a method for forming a skeleton.

Method (A) includes, for example, the following methods.

The compound of formula (1) wherein R ⁶ is a carboxyl group can be obtained by hydrolyzing the compound of formula (1) wherein R ⁶ is -COOR ¹¹ .

One method for obtaining a compound of the general formula (1) wherein R ⁶ is a C-bonded tetrazolyl group is carried out by using a compound of the general formula (1) wherein R ⁶ is a cyano group at toluene, xylene, Sodium azide, ammonium azide (preferably made by itself from sodium azide and ammonium chloride), or tributyltin azide (preferably azide) in anhydrous solvents such as dimethoxyethane or tetrahydrofuran Reacting with a suitable azide compound such as is prepared by itself from sodium and tributyltin chloride.

In the case of using tributyltin azide, the tributyltin group is removed by treating the resulting compound with a basic aqueous solution or an acidic aqueous solution after the reaction.

R ⁶ is a tetrazolyl group C- bond Another way to obtain a compound of formula (1) are to be found in the carboxyl group of the compound represented by the general formula (1) R ⁶ is a carboxyl group [JV Duncia et al, J. Org . Chem., 56, 2395 (1991)], after conversion to acid chlorides or active esters, the resulting compound is reacted with 2-aminopropionitrile and the compound is then triphenylphosphine, diethylazo Consisting of reacting with dicarboxylates and azylated trimethylsilyl.

Method (B) is typically carried out by converting functional groups and substituents. In this method, the compound of the general formula (1) converts the functional group and the substituent of the analogous compound having the same functional group and substituent as the compound of the general formula (1) but outside the range of the compound of the general formula (1). Are synthesized.

Representative examples of conversion of functional groups and the like include deprotecting functional groups protected by protecting groups. In addition, the compounds of formula (1) can be synthesized by converting from a similar compound having an amino group or a mercapto group in the position corresponding to R ^6, a group as defined for the amino group or mercapto group in R ^6. Examples of the method (B) include the following.

R ⁶ is a compound of C- bond tetrazolyl group general formula (1), and the like compounds having a group R ⁶ C- bond protected by a suitable protecting group in the position corresponding to a tetrazolyl can be obtained by deprotection. In this case, the protecting group includes, for example, a triphenylmethyl group and a cyanoethyl group. Deprotection operations are described, for example, in TW Greene, Protective Groups in Organic Synthesis, John Wiley and Sons, Inc. (1981), such as the conventional operation.

Compounds of the general formula (1) wherein R ⁶ is -NHSO ₂ CF ₃ are analogous compounds having an amino group at a position corresponding to R ⁶ in a suitable solvent such as dichloromethane in the presence of a suitable base such as triethylamine It can be obtained by reacting romethanesulfonic acid with anhydride.

Analogous compounds having an amino group at a position corresponding to R ⁶ protect the other functional groups with protecting groups, if necessary, and then, in the presence of a base such as triethylamine, in an alcohol solvent such as t-butyl alcohol. Phosphoryl was used to obtain carbamate by Curtius rearrangement from a compound of formula (1) wherein R ⁶ is a carboxyl group, and the carbamate was reacted with hydrochloric acid in a solvent such as ethanol. It can synthesize | combine by acid hydrolysis.

Compounds of formula (1) wherein R ⁶ is -SO ₃ are analogous to those having mercapto groups in positions corresponding to R ⁶ by oxidizing the mercapto group with a suitable oxidizing agent such as hydrogen peroxide, m-chloroperoxybenzoic acid or potassium permanganate It can be prepared from a compound. The analogous compound which has a mercapto group in the position corresponding to R <^6> can be synthesized by the following method (C), for example.

Method (C) involves the reaction of skeleton formation from which a compound of formula (1) and analogous compounds thereof can be obtained. Representative skeletal formation reactions are reactions of a compound of the following general formula (4) with a compound of the following general formula (5) or (6).

[Wherein L and R ²⁴ to R ²⁸ are as defined above]

[Wherein, R ²¹ to R ²³ are as defined above]

[Wherein, R ²¹ to R ²³ are as defined above]

The backbone of isoindazole compound (1) is a compound of formula (4) wherein N, in the presence of a base such as sodium hydride, sodium carbonate, potassium carbonate or sodium methoxide at a temperature between 0 ° C. and the reflux temperature of the solvent, Formed by reacting with imidazole of formula (5) or imidazopyridine of formula (6) in an aprotic solvent such as N-dimethylformamide, N, N-dimethylacetamide, tetrahydrofuran or dioxane do.

When synthesizing the isindazole compound (1), R ¹ to R ⁸ are not necessarily the same throughout the synthesis from the starting material to the final product. Sometimes the transformations illustrated below are necessary to introduce the final product.

Method (C) will describe, by way of example, an intermediate compound in which R ²¹ to R ²⁸ excluding R ²⁶ are the same as the corresponding R ¹ to R ⁸ (excluding R ⁶ ) of General Formula (1).

The isoindazole compound of formula (1) wherein R ⁶ is a C-linked tetrazolyl group, wherein the compound of formula (4) wherein R ²⁶ is a protective C-linked tetrazolyl group is hydrogenated at a temperature between 0 ° C. and the reflux temperature of the solvent. In aprotic solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, tetrahydrofuran or dioxane in the presence of a base such as sodium, sodium carbonate, potassium carbonate or sodium methoxide It can be obtained by reacting with imidazole of) or imidazopyridine of formula (6).

Otherwise, the compound of formula (4), wherein R ²⁶ is a protective C-linked tetrazolyl group, may react with a phase transfer catalyst (e.g. Aliquat 336) such as tetra alkyl ammonium at a temperature between 0 ° C and the reflux temperature of the solvent. In the presence of a basic aqueous solution such as aqueous sodium hydroxide solution or aqueous potassium hydroxide solution and a suitable organic solvent such as methylene chloride, can be obtained by reacting with imidazole of formula (5) or imidazopyridine of formula (6) have.

The intermediate compound of the general formula (4) can be prepared, for example, by converting the 5-position methyl group of the compound of the following general formula (7) to —CH ₂ L (L is a leaving group as defined above).

[Wherein, R ²⁴ to R ²⁸ are as defined above]

Substituents in formula (7) Although identically defined as in formula (4) (ie, R ²⁴ to R ²⁸ are common to both formulas), this corresponds to the corresponding R ⁴ to R of formula (1). As long as it can be converted to ⁸ , it is not limited thereto. Similarly to the general formulas (8) to (10) described below, the substituents are assumed to be the same as the substituents of the general formula (4).

For example, when L is chlorine, bromine or iodine, the compound of formula (7) is replaced with N-chlorosuccinimide, N-bromo in the presence of a radical initiator such as azobisisobutyronitrile or dibenzoyl peroxide. Reaction with succinimide or N-iodine succinimide converts to the compound of formula (4). Similar reactions can be carried out by light irradiation instead of using the radical initiators described above.

When R ²⁵ is chlorine, bromine or iodine in the compound of formula (4), L and R ²⁵ may be the same, and they are compounds of formula (7) wherein R ²⁵ is a hydrogen atom under the same reaction conditions as described above. By reacting chlorine, bromine or iodine at the same time.

The compound of general formula (7) can be prepared by reacting the compound of general formula (8) with a deoxygenating agent such as triethylphosphite.

[Wherein, R ²⁴ to R ²⁸ are as defined above]

R ²⁶ is converted to its substituents from the triphenylmethyl group or a cyano compound of group C- bond protected by a suitable protecting group such as a tetrazolyl group Formula (7) Formula (7) the compounds R ²⁶ is a cyano group of Can be synthesized.

For example, it is possible to prepare a compound of formula (7) wherein R ²⁶ is a cyano group at the reflux temperature of or near the solvent, sodium azide, azization in anhydrous solvents such as toluene, xylene, dimethoxyethane or tetrahydrofuran With suitable azide compounds such as ammonium (preferably made from sodium azide and ammonium chloride) or tributyltin azide (preferably made from sodium azide and tributyltin chloride) It can be obtained by reacting (when using tributyltin azide, after the reaction, the resulting compound is treated with a basic or acidic aqueous solution to remove the tributyltin group) and attaching a protecting group thereto.

Otherwise, R ²⁶ is synthesized from a triphenylmethyl group or a cyano compound of the C- bond protected by a suitable protecting group such as a tetrazolyl group resulting from the general formula (7) compounds of the general formula (7) R ²⁶ is a carboxyl group of the By JV Duncia et al, J. Org. Chem., 56, 2395 (1991). Ie converting the carboxyl group at the R ²⁶ position to an acid chloride or active ester and reacting the resulting compound with 2-aminopropionitrile, which is added with triphenylphosphine, diethylazodicarboxylate and azylated trimethylsilyl It can be obtained by reacting with and then attaching a protecting group.

The compound of formula (8) is formulated in the following formula (10) in a suitable solvent such as benzene or toluene while removing water in the presence of a dehydrating agent such as molecular sieve or by azeotropic dehydration. It can be obtained by reacting with a compound of.

Wherein R ²⁴ and R ²⁵ are as defined above.

[Wherein, R ²⁶ to R ²⁸ are as defined above]

Compounds of formula (9) are described, for example, in T. G. Miller et al, J. Org. Chem. 45, 1334 (1980)].

Among the compounds of the formula (10), a compound wherein R ²⁶ is a C-linked tetrazolyl group protected with a suitable protecting group such as triphenylmethyl group or cyanoethyl group is an amino group of the compound of formula (10) wherein R ²⁶ is a cyano group. Is protected with an appropriate protecting group and the compound is dissolved in anhydrous solvents such as toluene, xylene, dimethoxyethane or tetrahydrofuran at or near the reflux temperature of the solvent, preferably sodium azide or ammonium azide (preferably sodium azide). And tributyltin azide (preferably prepared from ammonium chloride) or tributyltin azide (preferably prepared from sodium azide and tributyltin chloride itself) When using, after the reaction, the resulting compound is treated with a basic or acidic aqueous solution to remove the tributyltin group), It can be obtained by attaching an appropriate protecting group to the resulting tetrazole group and deprotecting the amino group.

Among the compounds of the general formula (10), compounds in which R ²⁶ is a C-linked tetrazolyl group protected with a suitable protecting group such as triphenylmethyl group or cyanoethyl group are described by JV Duncia et al., J. Org. Chem., 56, 2395 (according to 1991 (), the amino group of the compound of formula (10) wherein R ²⁶ is a carboxyl group is protected with an appropriate protecting group, the carboxyl group is converted to an acid chloride or an active ester, and the resulting compound is 2 By reacting with aminopropionitrile and further reacting with triphenyl phosphine, diethylazodicarboxylic acid salt and trimethylsilyl azide, attaching the appropriate protecting group to the resulting tetrazole group and then deprotecting the amino group Can be obtained.

The imidazole of the general formula (5) can be synthesized, for example, according to the method of Japanese Patent Laid-Open No. 501020/1991 or a method equivalent thereto.

The imidazopyridine of the general formula (6) can be synthesized according to, for example, the method of Japanese Patent Laid-Open No. 95181/1991 or equivalent thereto.

Isoindazole compound (1) of the present invention can be separated and purified by conventional methods such as extraction, crystallization, fractional crystallization, recrystallization and chromatography.

Isoindazole compound (1) obtained as above can be converted into its salt by a conventional method.

Isoindazole compound (1) and salts thereof of the present invention exhibit excellent angiotensin II antagonism and have low toxicity. Thus, they are useful as angiotensin II antagonists used for the treatment or prevention of angiotensin II-interventional diseases such as hypertension (eg, essential hypertension, nephrotic hypertension) and heart failure.

Isoindazole compound (1) and salts thereof of the present invention are not only used as a prophylactic and / or therapeutic agent for cardiac disorders such as angina pectoris, arrhythmia and myocardial infarction, aldosteroneemia, cerebral circulation diseases, senile dementia, eye diseases such as glaucoma, etc. It is expected to be useful as a diagnostic drug for testing the Lenin-Angiotensin family.

For the treatment or prophylaxis, the isoindazole compound (1) or salt thereof of the present invention can be used for the pharmaceutically acceptable carrier (oral, parenteral administration or use) of the isoindazole compound (1) or salt thereof (active ingredient). In the form of conventional pharmaceutical preparations containing as a mixture with a suitable organic or inorganic, solid or liquid excipient, etc.). The pharmaceutical preparations may be in solid form such as tablets, granules, powders or capsules or in liquid form such as liquids, suspensions, syrups, emulsions, lemonades and the like.

If necessary, supplements, stabilizers, wetting agents, and lactose, citric acid, tartaric acid, stearic acid, magnesium stearate, clay, sucrose, corn starch, talc, gelatin, agar, pectin, peanut oil, olive oil, cacao may be used if necessary. Oil, other conventional additives such as ethylene glycol, and the like can be added.

The dosage of isoindazole compound (1) or salts thereof generally varies daily, depending on the age, symptoms, type of disease and condition of the patient, type of isoindazole compound (1) or salts thereof, and the like. 0.01 mg to about 500 mg is administered. When treating various diseases, the isoidazole compound (1) or salt thereof of the present invention may be used in an average dose of about 0.05 mg, 0.1 mg, 0.25 mg, 0.5 mg, 1 mg, 20 mg, 50 mg or 100 mg. have.

The invention is illustrated in detail by the examples which follow, without being restricted thereto.

Reference Example 1

Synthesis of 5-methyl-2-nitrobenzaldehyde

Pyridinium chlorochromium (25.0 g, 116 mmol) is added to methylene chloride (65 mL) with stirring, followed by 5-methyl-2-nitrobenzyl alcohol (12.9 g, 77.3 mmol). The mixture is stirred at rt for 15 h and diethyl ether (155 ml) is added. The ether layer is removed by decantation. Diethyl ether (30 mL) was added to the residue, and the ether layer was removed by decantation (three times). The ether layers are combined and passed through 15.5 g of silica gel. The resulting solution is concentrated and flash chromatography on silica gel using a mixed solvent of hexane / ethyl acetate (8: 1) to give 10.6 g of 5-methyl-2-nitrobenzaldehyde.

Reference Example 2

Synthesis of N- (5-methyl-2-nitrobenzylidene) ethyl anthranilate

Toluene (30 mL) is added to 5-methyl-2-nitrobenzaldehyde (4.26 g, 25.8 mmol) obtained in Reference Example 1, and the mixture is stirred. Ethyl anthranilate (4.26 g, 25.8 mmol) is added thereto. The mixture is heated to reflux for 10 hours and then cooled. Next, molecular sieve 5A (20.6 g) is added and the mixture is left overnight. The mixture is filtered and the cake is washed five times with 20 ml of toluene. The filtrate is concentrated, 25 ml of toluene is added to dissolve and hexane (25 ml) is added with stirring. The precipitated solid is filtered off and washed twice with 30 ml of a mixed solvent of toluene / hexane (2: 1). The cake was dried in vacuo to afford 3.11 g of ethyl N- (5-methyl-2-nitrobenzylidene) anthranilate.

Reference Example 3

Synthesis of 2- (5-methyl-2H-indazol-2-yl) ethyl benzoate

Triethyl phosphite (5.8 mL, 34 mmol) is added to N- (5-methyl-2-nitrobelzylidene) anthranilate (3.10 g, 9.93 mmol) obtained in Reference Example 2. The mixture is heated to reflux for 4 hours and the triethyl phosphite is evaporated under reduced pressure. The residue is purified by flash chromatography on silica gel using a mixed solvent of hexanes / ethyl acetate (5: 1) to afford 1.79 g of ethyl 2- (5-methyl-2H-indazol-2-yl) benzoate. .

Reference Example 4

Synthesis of 2- (3-bromo-5-methyl-2H-indazol-2-yl) ethyl benzoate

Carbon tetrachloride (26 mL) is added to 2- (5-methyl-2H-indazol-2-yl) ethyl benzoate (1.43 g, 510 mmol) obtained in Reference Example 3 and the mixture is stirred. N-bromosuccinimide (0.908 g, 5.10 mmol) and azobisisobutyronitrile (78 mg, 0.48 mmol) were added thereto and the mixture was heated to reflux for 3 hours. After cooling, the mixture is filtered and the cake is washed twice with carbon tetrachloride (5 mL). The filtrate was concentrated and subjected to flash chromatography on silica gel using a mixed solvent of hexane / ethyl acetate (8: 1 to 3: 1) to give 2- (3-bromo-5-methyl-2H-indazole- 2-yl) 1.47 g of ethyl benzoate is obtained.

Reference Example 5

Synthesis of 2- [3-bromo-5- (bromomethyl) -2H-indazol-2-yl] ethyl benzoate

Carbon tetrachloride (130 ml) was added to 2- (5-methyl-2H-indazol-2-yl) ethyl benzoate (7.14 g, 25.5 mmol) obtained in Reference Example 3, and then N-bromosuccicin was added thereto. Imide (4.62 g, 26.0 mmol) is added. The mixture is stirred for 6 hours and N-bromosuccinimide (0.36 g, 2.04 mmol) is added. After reacting for 1 hour, N-bromosuccinimide (4.54 g, 25.5 mmol) and azobisisobutyronitrile (0.21 g, 1.275 mmol) were added thereto, and the mixture was refluxed for 3.5 hours, Cool. Dichloromethane (260 mL) and water (130 mL) are added there and liquid-separated, and an aqueous layer is extracted with dichloromethane (65 mL). The organic layer is washed with water (130 mL), dried over magnesium sulfate and filtered. The filtrate is concentrated by evaporator. The residue was subjected to flash chromatography on silica gel using a mixed solvent of hexane / ethyl acetate (8: 1) to give 2- [3-bromo-5- (bromomethyl) -2H-indazol-2- General] 1.95 g of ethyl benzoate is obtained.

Reference Example 6

Synthesis of 2- [N- (5-methyl-2-nitrobenzylidene) amino] benzonitrile

Toluene (167 mL) and 2-aminobenzonitrile (19.7 g, 167 mmol) were added to the 5-methyl-2-nitrobenzaldehyde (27.5 g. 167 mmol) obtained in Reference Example 1, and the mixture was stirred and refluxed for 14 hours. Then cool. The resulting crystals were filtered off and washed twice with a mixed solvent of hexane / toluene (2: 1, 150 mL) and hexane (150 mL) to give 2- [N- (5-methyl-2-nitrobenzylidene) amino 27.5 g of benzonitrile are obtained. In addition, the solid precipitated from the filtrate was filtered off and washed with hexane (100 mL and 50 mL) to give 10.0 g of the title compound.

Reference Example 7

Synthesis of 2- (5-methyl-2H-indazol-2-yl) benzonitrile

Triethyl phosphite (82.8 ml, 483 mmol) was added to 2- [N- (5-methyl-2-nitrobenzylidene) amino] benzonitrile (37.5 g, 141 mmol) obtained in Reference Example 6, and the mixture was Cool by reflux for 3 hours. The resulting solid was filtered off, washed twice with ethyl acetate (80 mL) and twice with methanol (20 mL) and dried in vacuo to give 10.2 g of 2- (5-methyl-2H-indazol-2-yl) benzonitrile. To obtain.

Reference Example 8

Synthesis of 5- [2- (5-methyl-2H-indazol-2-yl) phenyl] -2- (triphenylmethyl) -2H-tetrazole

Toluene (11.3 ml) is added to 2- (5-methyl-2H-indazol-2-yl) benzonitrile (3.53 g, 15.1 mmol) obtained in Reference Example 7, and the mixture is stirred. To this was further added sodium azide (0.982 g, 15.1 mmol) and tributyltin chloride (4.46 mL, 16.4 mmol) and the mixture was heated to reflux for 45 hours. The mixture is cooled and diluted with toluene (4 mL). 10N aqueous sodium hydroxide solution (1.8 ml) and trityl chloride (4.36 g, 15.6 mmol) were added thereto under stirring. Water (10 mL) is added and the mixture is stirred at rt for 1.5 h, then hexane (20 mL) is added. The solid is filtered off and washed sequentially with water (15 mL) twice with a mixed solvent of hexane / toluene (2: 1, 15 mL) and hexane (15 mL). The cake is dried in vacuo to afford 8.0 g of 5- [2- (5-methyl-2H-indazol-2-yl) phenyl] -2- (triphenylmethyl) -2H-tetrazole.

Reference Example 9

Synthesis of 5- {2- [3-bromo-5- (bromomethyl) -2H-indazol-2-yl] phenyl} -2- (triphenylmethyl) -2H-tetrazole

5- [2- (5-methyl-2H-indazol-2-yl) phenyl] -2- (triphenylmethyl) -2H-tetrazole (14.5 g, 30.0 mmol) obtained in Reference Example 8 was referred to. 5- {2- [3-bromo-5- (bromomethyl) -2H-indazol-2-yl] phenyl} -2- (triphenylmethyl) -2H-tetra by treatment in the same manner as in 5 3.67 g of sol are obtained.

Example 1

2-butyl-4-chloro-1- [3-bromo-2- (2-ethoxycarbonylphenyl) -2H-indazol-5-yl] methyl-1H-imidazole-5-carbaldehyde and Synthesis of 2-butyl-4-chloro-1- [2- (2-ethoxycarbonylphenyl) -2H-indazol-5-yl] methyl-1H-imidazole-5-carbaldehyde

Carbon tetrachloride (17 ml) was added to 2- (5-methyl-2H-indazol-2-yl) benzoate (0.95 g. 3.4 mmol) obtained in Reference Example 3, and then N-bromosuccicin was added thereto. Imide (0.60 g, 3.4 mmol) and azobisisobutyronitrile (56 mg, 0.34 mmol) are added. The mixture is reacted under reflux for 3 hours, then cooled and N-bromosuccinimide (0.12 g, 0.68 mmol) and azobisisobutyronitrile (11 mg, 0.068 mmol) are added. The mixture is refluxed for 1.5 hours and cooled. The mixture is filtered and the filtrate is concentrated by evaporator. The residue was dissolved in N, N-dimethylformamide (8 mL), 2-butyl-4-chloro-1H-imidazole-5-carbaldehyde (0.45 g, 2.4 mmol) and potassium carbonate (0.37 g, 2.6 mmol) is added and then stirred at room temperature for 2 days. The mixture is filtered and the cake is washed twice with chloroform (5 mL). After distilling N, N-dimethylformamide from the filtrate, the residue was subjected to flash chromatography on silica gel using a mixed solvent of hexane / ethyl acetate (3: 1 to 2: 1) to 2-butyl-4-. 0.22 g of chloro-1- [3-bromo-2- (2-ethoxycarbonylphenyl) -2H-indazol-5-yl] methyl-1H-imidazole-5-carbaraldehyde, and 2-butyl- 0.2 g of 4-chloro-1- [2- (2-ethoxycarbonylphenyl) -2H-indazol-5-yl] methyl-1H-imidazole-5-carbaldehyde are obtained.

NMR (270MHz, CDCl ₃ )

2-butyl-4-chloro-1- [3-bromo-2- (2-ethoxycarbonylphenyl) -2H-indazol-5-yl] methyl-1H-imidazole-5-carbaldehyde: δ 9.8 (s, 1H): 7.1 to 8.2 (m, 7H): 5.6 (s, 2H): 4.0 (q, J = 7 Hz, 2H): 2.7 (t, J = 8 Hz, 2H): 1.7 ( m, 2H): 1.3 (m, 2H): 0.9 (t, J = 7 Hz, 3H): 0.8 (t, J = 7 Hz, 3H)

2-butyl-4-chloro-1- [2- (2-ethoxycarbonylphenyl) -2H-indazol-5-yl] methyl-1H-imidazole-5-carbaldehyde: δ 9.8 (s, 1H): 8.2 (s, 1H): 7.1 to 7.9 (m, 7H): 5.6 (s, 2H): 4.0 (q, J = 7 Hz, 2H): 2.7 (t, J = 8 Hz, 2H): 1.7 (m, 2H): 1.3 (m, 2H): 0.9 (m, 6H).

Example 2

1- [3-brobo-2- (2-ethoxycarbonylphenyl) -2H-indazol-5-yl] methyl-2-butyl-4-chloro-5- (hydroxymethyl) -1H-already Synthesis of Dazole

2butyl-4-chloro-1- [3-bromo-2- (2-ethoxycarbonylphenyl) -2H-indazol-5-yl] methyl-1H-imidazole-5 obtained in Example 1 Carbaldehyde (0.122 g, 0.224 mmol) is dissolved in a mixed solvent of tetrahydrofuran (1.2 mL) and methanol (1.2 mL) and the mixture is stirred. Sodium borohydride (8.5 mg, 0.224 mmol) is added thereto, and the mixture is allowed to react at room temperature for 5 minutes. The mixture is concentrated by evaporator and partitioned into saturated aqueous sodium hydrogen carbonate solution (2.5 mL). The organic layer is separated and the aqueous layer is further extracted with ethyl acetate (2.5 mL). The organic layers were combined, dried over magnesium sulfate and filtered. The solvent was evaporated in vacuo to give 1- [3-bromo-2- (2-ethoxycarbonylphenyl) -2H-indazol-5-yl] methyl-2-butyl-4-chloro-5- (hydroxymethyl 0.110 g of) -1H-imidazole is obtained.

Example 3

Synthesis of 2-butyl-4-chloro-1- [2- (2-ethoxycarbonylphenyl) -2H-indazol-5-yl] methyl-5- (hydroxymethyl) -1H-imidazole

2-Butyl-4-chloro-1- [2- (2-ethoxycarbonylphenyl) -2H-indazol-5-yl] methyl-1H-imidazole-5-carbaldehyde obtained in Example 1 (0.133 g, 0.286 mmol) is dissolved in a mixed solvent of tetrahydrofuran (1.5 mL) and methanol (1.5 mL) and the mixture is stirred. Sodium borohydride (11 mg, 0.286 mmol) is added thereto and the mixture is allowed to react at room temperature for 5 minutes. The mixture is concentrated in an evaporator and partitioned between saturated aqueous sodium bicarbonate solution (3 mL) and ethyl acetate (3 mL). The organic layer is separated and the aqueous layer is further extracted with ethyl acetate (3 mL). The combined organic layers are dried over magnesium sulfate and filtered. The solvent was evaporated in vacuo to give 2-butyl-4-chloro-1- [2- (2-ethoxycarbonylphenyl) -2H-indazol-5-yl] methyl-5-yl] methyl-5- (hydroxy 0.116 g of methyl) -1H-imidazole is obtained.

Example 4

Synthesis of 1- [3-bromo-2- (2-carboxyphenyl) -2H-indazol-5-yl] methyl-2-butyl-4-chloro-5- (hydroxymethyl) -1H-imidazole

1- [3-bromo-2- (2-ethoxycarbonylphenyl) -2H-indazol-5-yl] methyl-2-butyl-4-chloro-5- (hydroxy obtained from Example 2 To methyl) -1H-imidazole (106 mg, 0.205 mmol), ethanol (1.2 ml), ion-exchanged water (0.3 ml) and potassium hydroxide (45 mg) were added, and the mixture was stirred at room temperature for 1 day. The mixture is concentrated in an evaporator and partitioned into ion exchanged water (2.5 mL) and diethyl ether (5 mL). The aqueous layer is separated and concentrated hydrochloric acid is added dropwise thereto to adjust the pH to 5-6. The resulting solid is filtered off and washed twice with ion exchanged water (1 mL). One drop of concentrated hydrochloric acid is added to the filtrate to precipitate a solid, which is washed with water and then combined with a solid obtained in advance. It was vacuum dried at 37 ° C. for 2 days to allow 1- [3-bromo-2- (2-carboxyphenyl) -2H-indazol-5-yl] methyl-2-butyl-4-chloro-5- (hydroxy 56 mg of methyl) -1H-imidazole are obtained.

Example 5

Synthesis of 2-butyl-4-chloro-1- [2- (2-carboxyphenyl) -2H-indazol-5-yl] methyl-5- (hydroxymethyl) -1H-imidazole

2-Butyl-4-chloro-1- [2- (2-ethoxycarbonylphenyl) -2H-indazol-5-yl] methyl-5- (hydroxymethyl) -1H- obtained in Example 3 To imidazole (116 mg, 0.248 mmol) is added ethanol (1.5 mL), ion-exchanged water (0.3 mL) and potassium hydroxide (42 mg) and the mixture is stirred at room temperature for 1.5 hours. The mixture is concentrated in an evaporator and partitioned into ion exchanged water (2.5 mL) and diethyl ether (5 mL). The aqueous layer is separated and the pH is adjusted to 2 by dropwise addition of concentrated hydrochloric acid. The resulting solid is filtered off and washed three times with ion exchanged water (1 mL). The solid was dried in vacuo at 37 ° C. overnight to afford 2-butyl-4-chloro-1- [2- (2-carboxyphenyl) -2H-indazol-5-yl] methyl-5- (hydroxymethyl) -1H- 58 mg of imidazole are obtained.

Example 6

Synthesis of 2-butyl-4-chloro-1- [3-bromo-2- (2-carboxyphenyl) -2H-indazol-5-yl] methyl-1H-imidazole-5-carbaldehyde

2-Butyl-4-chloro-1- [3-bromo-2- (2-ethoxycarbonylphenyl) -2H-indazol-5-yl] methyl-1H-imidazole- obtained in Example 1 Ethanol (1.2 mL), ion-exchanged water (0.3 mL) and potassium hydroxide (28 mg) were added to 5-carbaldehyde (101 mg, 0.186 mmol), and the mixture was stirred at room temperature for 1 day. The mixture is concentrated in an evaporator and partitioned between ion exchanged water (2.5 mL) and diethyl ether (5 mL). The aqueous layer is separated and the pH is adjusted to 5 by dropwise addition of concentrated hydrochloric acid. The resulting solid is filtered off and washed three times with ion exchanged water (1 mL). The solid was dried in vacuo at 37 ° C. overnight to afford 2-butyl-4-chloro-1- [3-bromo-2- (2-carboxyphenyl) -2H-indazol-5-yl] methyl-1H-imidazole- 72 mg of 5-carbaldehyde are obtained.

Example 7

Synthesis of 2-butyl-4-chloro-1- [2- (2-carboxyphenyl) -2H-indazol-5-yl] methyl-1-H-imidazole-5-carbaldehyde

2-Butyl-4-chloro-1- [2- (2-ethoxycarboxyphenyl) -2H-indazol-5-yl] methyl-1-H-imidazole-5-carbal obtained in Example 1 To dehydrate (61 mg, 0.13 mmol) is added ethanol (0.8 mL), ion-exchanged water (0.2 mL) and potassium hydroxide (28 mg), and the mixture is stirred at room temperature for 2 hours. The mixture is concentrated in an evaporator and partitioned between ion exchanged water (2.5 mL) and diethyl ether (5 mL). The aqueous layer is separated and pH is adjusted to 1 by dropwise addition of concentrated hydrochloric acid. The resulting solid is filtered off and washed three times with ion exchanged water (1 mL). The solid was dried in vacuo at 37 ° C. overnight to afford 2-butyl-4-chloro-1- [2- (2-carboxyphenyl) -2H-indazol-5-yl] methyl-1-H-imidazole-5-carbox Obtain 36 mg of aldehyde.

Example 8

2-butyl-4-chloro-1- [3-bromo-2- (2-ethoxycarbonylphenyl) -2H-indazol-5-yl] methyl-1H-imidazole-5-carboxylic acid methyl And 2-butyl-5-chloro-1- [3-bromo-2- (2-ethoxycarbonylphenyl) -2H-indazol-5-yl] methyl-1H-imidazole-4-carboxylic acid Methyl synthesis

2- [3-bromo-5- (bromomethyl) -2H-indazol-2-yl] benzoate (0.356 g, 0.813 mmol) obtained in Reference Example 5 was diluted with N, N-dimethylformamide (4 Ml). To the mixture are added 2-butyl-4-chloro-1H-imidazole-5-carboxylic acid methyl (0.159 g, 0.732 mmol) and potassium carbonate (0.112 g, 0.813 mmol) and the mixture is stirred at room temperature for 1 day. . The mixture is filtered and the cake is washed twice with chloroform (5 mL). N, N-dimethylformamide was distilled from the filtrate, and the resulting mixture was subjected to flash chromatography on silica gel using a mixed solvent of hexane / ethyl acetate (3: 1 to 1: 1) to 2-butyl-4. 0.148 g of -chloro-1- [3-bromo-2- (2-ethoxycarbonylphenyl) -2H-indazol-5-yl] methyl-1H-imidazole-5-carboxylic acid methyl and 2- Butyl-5-chloro-1- [3-bromo-2- (2-ethoxycarbonylphenyl) -2H-indazol-5-yl] methyl-1H-imidazole-4-carboxylic acid methyl 26 mg To obtain.

NMR (270MHz, CDCl ₃ )

2-butyl-4-chloro-1- [3-bromo-2- (2-ethoxycarbonylphenyl) -2H-indazol-5-yl] methyl-1H-imidazole-5-carboxylic acid methyl : δ 8.1 (d, J = 8 Hz, 1H): 7.0 to 7.7 (m, 6H): 5.6 (s, 1H): 4.0 (q, J = 7 Hz, 2H): 3.8 (s, 3H): 2.7 (m, 2H): 1.7 (m, 2H): 1.4 (m, 2H): 0.9 (t, J = 7 Hz, 3H): 0.8 (t, J = 7 Hz, 3H).

2-Butyl-5-chloro-1- [3-bromo-2- (2-ethoxycarbonylphenyl) -2H-indazol-5-yl] methyl-1H-imidazole-4-carboxylic acid methyl : δ 8.1 (d, J = 8 Hz, 1H): 7.0 to 7.7 (m, 6H): 5.3 (s, 1H): 4.0 (q, J = 7 Hz, 2H): 3.9 (s, 3H): 2.7 (m, 2H): 1.7 (m, 2H): 1.4 (m, 2H): 0.9 (t, J = 7 Hz, 3H): 0.8 (t, J = 7 Hz, 3H).

Example 9

Synthesis of 1- [3-bromo-2- (2-carboxyphenyl) -2H-indazol-5-yl] methyl-2-butyl-4-chloro-1H-imidazole-5-carboxylic acid disodium

2-Butyl-4-chloro-1- [3-bromo-2- (2-ethoxycarbonylphenyl) -2H-indazol-5-yl] methyl-1H-imidazole- obtained in Example 8 Ethanol (5.5 mL) and 1N aqueous sodium hydroxide solution (1.38 mL) are added to 5-carboxylic acid methyl (0.132 g, 0.230 mmol), and the mixture is stirred at room temperature for 1 day. The mixture is concentrated in an evaporator, to which ion-exchanged water (5 ml) is added and then stirred. Concentrated hydrochloric acid is added dropwise there, and pH is adjusted to 5-6. The resulting solid is filtered off and washed three times with ion exchanged water (2.5 mL). To the solid obtained by vacuum drying at 37 DEG C for 2 days, 2 equivalents of an aqueous N / 10 sodium hydroxide solution was added to dissolve. The solution was lyophilized to yield 1- [3-bromo-2- (2-carboxyphenyl) -2H-indazol-5-yl] methyl-2-butyl-4-chloro-1H-imidazole-5-carboxyl 0.104 g sodium diacid is obtained.

Example 10

Synthesis of 2-butyl-5-chloro-1- [3-bromo-2- (2-carboxyphenyl) -2H-indazol-5-yl] methyl-1H-imidazole-4-carboxylic acid disodium

2-Butyl-5-chloro-1- [3-bromo-2- (2-ethylcarbonylphenyl) -2H-indazol-5-yl] methyl-1H-imidazole-4 obtained in Example 8 Methyl carboxylic acid (26 mg) was treated in the same manner as in Example 9 to give 2-butyl-5-chloro-1- [3-bromo-2- (2-carboxyphenyl) -2H-indazole- 21 mg of 5-yl] methyl-1H-imidazole-4-carboxylic acid is obtained.

Example 11

1-{[3-bromo-2- [2- (2- (triphenylmethyl) -2H-tetrazol-5-yl) phenyl] -2H-indazol-5-yl] methyl} -2-butyl Synthesis of 4-chloro-1H-imidazole-5-carbaldehyde

5- {2- [3-bromo-5- (bromomethyl) -2H-indazol-2-yl] phenyl} -2- (triphenylmethyl) -2H-tetrazole obtained in Reference Example 9 ( 1.00 g, 1.48 mmol) was reacted with 2-butyl-4-chloro-1H-imidazole-5-carbaldehyde (0.248 g, 1.33 mmol) in the same manner as in Example 8 to give 1-{[3- Bromo-2- [2- (2- (triphenylmethyl) -2H-tetrazol-5-yl) phenyl] -2H-indazol-5-yl] methyl} -2-butyl-4-chloro-1H 0.74 g of -imidazole-5-carbaldehyde is obtained.

Example 12

1-{[3-bromo-2- [2- (1H-tetrazol-5-yl) phenyl] -2H-indazol-5-yl] methyl} -2-butyl-4-chloro-1H-imi Synthesis of Dazol-5-Carbaldehyde

Methanol (2 mL) was obtained by Example 1-{[3-bromo-2- [2-2- (triphenylmethyl) -2H-tetrazol-5-yl) phenyl] -2H-indazole -5-yl] methyl} -2-butyl-4-chloro-1H-imidazole-5-carbaldehyde 0.200 g, 0.256 mmol) and the mixture is stirred at 10 ° C. 2N hydrochloric acid (0.23 mL) is added thereto and the mixture is stirred at room temperature for 2 hours. Next, 2N hydrochloric acid (0.23 mL) and methanol (2.5 mL) are added thereto, and the mixture is stirred for 3 hours, followed by concentrated hydrochloric acid (2 mL) and the mixture is stirred for 15.5 hours. The pH is adjusted to 13 by addition of 10N aqueous sodium hydroxide solution and methanol is distilled off in the evaporator. The resulting solid is filtered off and the cake is washed twice with 1N sodium hydroxide (2.5 mL). The filtrate is washed with ether (5 ml) and the pH is adjusted to 4-5 by dropwise addition of concentrated hydrochloric acid with stirring. The resulting solid is filtered off and washed twice with ion exchanged water (5 mL). Vacuum dried at 37 ° C., 1-{[3-bromo-2- [2-1H-tetrazol-5-yl) phenyl] -2H-indazol-5-yl] methyl} -2-butyl-4 45 mg of -chloro-1H-imidazole-5-carbaldehyde is obtained.

Example 13

1-{[3-bromo-2- [2- (2- (triphenylmethyl) -2H-tetrazol-5-yl) phenyl] -2H-indazol-5-yl] methyl} -2-butyl Synthesis of -4-chloro-5- (hydroxymethyl) -1H-imidazole

1-{[3-bromo-2- [2- (2- (triphenylmethyl) -2H-tetrazol-5-yl) phenyl] 2H-indazol-5-yl] methyl obtained in Example 11 } -2-Butyl-4-chloro-1H-imidazole-5-carbaraldehyde (0.54 g, 0.690 mmol) is dissolved in tetrahydrofuran (7 mL) and the mixture is stirred. Sodium borohydride (26 mg, 0.690 mmol) is added thereto and the mixture is allowed to react at room temperature for 5 minutes. The mixture is concentrated in an evaporator and partitioned between saturated aqueous sodium hydrogen carbonate solution (5 mL) and dichloromethane (5 mL). The organic layer is separated and the aqueous layer is extracted with dichloromethane (5 ml). The combined organic layers are dried over magnesium sulfate and filtered. The solvent was evaporated in vacuo and the mixture was subjected to flash chromatography on silica gel using a mixed solvent of dichloromethane / methanol to give 1-{[3-bromo-2- [2- (2- (triphenylmethyl-2H 0.44 g of -tetrazol-5-yl) phenyl] -2H-indazol-5-yl] methyl} -2-butyl-4-chloro-5- (hydroxymethyl) -1H-imidazole are obtained.

Example 14

1-{[3-bromo-2- [2- (1H-tetrazol-5-yl) phenyl] -2H-indazol-5-yl] methyl} -2-butyl-4-chloro-5- ( Synthesis of hydroxymethyl) -1H-imidazole

1-{[3-brobo-2- [2- (2-triphenylmethyl) -2H-tetrazol5-yl) phenyl] -2H-indazol-5-yl] methyl in dichloromethane (8.4 mL) To a solution of 2-butyl-4-chloro-5- (hydroxymethyl) -1H-imidazole (obtained in Example 13) was added 14.7% hydrogen chloride solution (5.6 mL) in ethanol dropwise and the mixture was allowed to come to room temperature. Stir at 17 h. The mixture is concentrated in an evaporator, to which water (5 ml), 10 N aqueous sodium hydroxide solution (1.25 ml) and 1 N aqueous sodium hydroxide solution (5 ml) are added and then filtered. The cake is washed twice with water (5 ml) and the pH is adjusted to 4-5 by dropwise addition of concentrated hydrochloric acid to the filtrate with stirring. The resulting solid was filtered off, washed twice with ion exchanged water (2 mL) and then vacuum dried at 37 ° C. to give 1-{[3-bromo-2- [2- (1H-tetrazol-5-yl 11 mg)) phenyl] -2H-indazol-5-yl] methyl} -2-butyl-4-chloro-5- (hydroxymethyl) -1H-imidazole is obtained.

Example 15

Synthesis of 2-butyl-3- [3-bromo-2- (2-ethoxycarbonylphenyl) -2H-indazol-5-yl] methyl-3H-imidazo [4,5, -b] pyridine

Carbon tetrachloride (4 mL) was added to 2- (3-bromo-5-methyl-2H-indazol-2-yl) ethyl benzoate (0.300 g, 0.835 mmol) obtained in Reference Example 4, and the mixture was stirred. do. N-bromosuccinimide (0.149 g, 0.835 mmol) and azobisisobutyronitrile (14 mg, 0.0835 mmol) were added thereto, and the mixture was heated to reflux for 3.5 hours. After cooling, the mixture is filtered, the cake is washed with carbon tetrachloride (1 ml) and the filtrate is concentrated. The residue is then dissolved in DMF (dimethylformamide, 1 mL), which is a solution of 2-butyl-1H-imidazo [4,5-b] pyridine (0.117 g, 0.668 mmol) in DMF (2 mL). To the solution obtained by adding sodium hydride (27 mg, 0.668 mmol) and stirring for 30 minutes. The mixture is stirred at rt for 30 min, concentrated and partitioned between ethyl acetate (5 mL) and water (5 mL). The organic layer is washed twice with water (5 mL), dried over magnesium sulfate and filtered. The filtrate was concentrated and flash chromatographed on silica gel using a mixed solvent of hexane / ethyl acetate (1: 2) to give 2-butyl-3- [3-bromo-2- (2-ethoxycarbonylphenyl 0.144 g))-2H-indazol-5-yl] methyl-3H-imidazo [4,5, -b] pyridine is obtained.

Example 16

Synthesis of 2-butyl-3- [3-bromo-2- (2-carboxyphenyl) -2H-indazol-5-yl] methyl-3H-imidazo [4,5-b] pyridine sodium salt

2-Butyl-3- [3-bromo-2- (2-ethoxycarbonylphenyl) -2H-indazole- obtained with ethanol (1.3 mL) and 1N aqueous sodium hydroxide solution (0.275 mL) in Example 15 To 5-yl] methyl-3H-imidazo [4,5-b] pyridine (0.144 g, 0.270 mmol), the mixture is stirred at room temperature for 16.5 hours and then heated to reflux for 3.5 hours. After cooling, sodium hydroxide (24 mg) is added thereto and the mixture is stirred at room temperature for 1 hour. After concentration, the mixture is partitioned between water (2.5 mL) and ether (5 mL). The pH is adjusted to 5 by dropwise addition of concentrated hydrochloric acid to the aqueous layer. The resulting solid is filtered off and washed twice with water (1 mL) and dried. Water and an equimolar amount of 1N sodium hydroxide aqueous solution are added there, and water is distilled off overnight by a centrifugal evaporator. The solid obtained was dried in vacuo at 37 ° C. overnight to afford 2-butyl-3- [3-bromo-2- (2-carboxyphenyl) -2H-indazol-5-yl] methyl-3H-imidazo [4 , 5-b] 89 mg of pyridine sodium salt.

Example 17

3- [3-bromo-2- (2-ethoxycarbonylphenyl) -2H-indazol-5-yl] methyl-5,7-dimethyl-2-ethyl-3H-imidazo [4,5- b] synthesis of pyridine

Carbon tetrachloride (2 mL) is added to 2- (3-bromo-5-methyl-2H-indazol-2-yl) ethyl benzoate (0.450 g, 1.25 mmol) obtained in Reference Example 4, and the mixture is stirred. . N-bromosuccinimide (0.223 g, 1.25 mmol) and azobisisobutyronitrile (21 mg, 0.125 mmol) were added thereto, and the mixture was heated to reflux for 3.5 hours. After cooling, it is filtered, the cake is washed with dichloromethane (2 mL) and the filtrate is concentrated. The residue is then dissolved in DMF (2 mL) and sodium hydride (40 mg, 1.00 mmol) is dissolved in 2-ethyl-5,7-dimethyl-1H-imidazo [4,5-b in DMF (4 mL). To pyridine (0.176 mg, 1.00 mmol) solution and then to solution obtained by stirring for 30 minutes. The mixture is stirred at rt for 30 min, concentrated and partitioned between ethyl acetate (10 mL) and water (10 mL). The organic layer is dried over magnesium sulfate and filtered. Concentrate the filtrate and perform flash chromatography on silica gel using a mixed solvent of hexane / ethyl acetate (2: 3) to give 3- [3-bromo-2- (2-ethoxycarbonylphenyl) -2H- 0.176 g of indazol-5-yl] methyl-5,7-dimethyl-2-ethyl-3H-imidazo [4,5-b] pyridine is obtained.

Example 18

3- [3-bromo-2- (2-carboxyphenyl) -2H-indazol-5-yl] methyl-5,7-dimethyl-2-ethyl-3H-imidazo [4,5-b] pyridine Synthesis of Sodium

Ethanol (1.3 mL), water (0.33 mL) and sodium hydroxide (39 mg, 0.986 mmol) obtained in Example 17, 3- [3-bromo-2- (2-ethoxycarbonylphenyl) -2H- Add to indazol-5-yl] methyl-5,7-dimethyl-2-ethyl-3H-imidazo [4,5-b] pyridine (0.175 mg, 0.329 mmol) and stir the mixture for 19 h at room temperature do. After concentration, partition into water (2.5 mL) and ether (5 mL). Under stirring, concentrated hydrochloric acid is added dropwise to the aqueous layer to adjust the pH to 5. The resulting solid is filtered off, washed twice with water (1 mL) and dried. Water and equimolar amounts of 1N aqueous sodium hydroxide solution are added thereto. The mixture was lyophilized to afford 3- [3-bromo-2- (2-ethoxycarbonylphenyl) -2H-indazol-5-yl] methyl-5,7-dimethyl-2-ethyl-3H-imidazo 106 mg of sodium [4,5-b] pyridine is obtained.

Example 19

3- [3-bromo-2- (2-ethoxycarbonylphenyl) -2H-indazol-5-yl] methyl-7-methyl-2-propyl-3H-imidazo [4,5-b] Synthesis of Pyridine

Carbon tetrachloride (4 mL) is added to 2- (3-bromo-5-methyl-2H-indazol-2-yl) ethyl benzoate (0.300 g, 0.835 mmol) obtained in Reference Example 4, and the mixture is stirred. . N-bromosuccinimide (0.149 g, 0.835 mmol) and azobisisobutyronitrile (14 mg, 0.0835 mmol) were added thereto, and the mixture was heated to reflux for 3.5 hours. After cooling, it is filtered and the cake is washed twice with dichloromethane (2.5 mL) to concentrate the filtrate. The residue was then dissolved in DMF (1 mL) and sodium hydroxide (27 mg, 0.668 mmol) was dissolved 7-methyl-2-propyl-1H-imidazo [4,5-b] pyridine in DMF (2 mL). (0.117 g, 0.668 mmol) is added to the solution and then to the solution obtained by stirring the solution for 30 minutes. The mixture is stirred at rt for 30 min, concentrated and partitioned between ethyl acetate (5 mL) and water (5 mL). The organic layer is washed twice with water (5 mL), dried over magnesium sulfate and filtered. Concentrate the filtrate and perform flash chromatography on silica gel using a mixed solvent of hexane / ethyl acetate (2: 3) to give 3- [3-bromo-2- (2-ethoxycarbonylphenyl) -2H- 70 mg of indazol-5-yl] methyl-7-dimethyl-2-methyl-2-propyl-3H-imidazo [4,5-b] pyridine is obtained.

Example 20

Synthesis of 3- [3-bromo-2- (2-carboxyphenyl) -2H-indazol-5-yl] methyl-7-methyl-2-propyl-3H-imidazo [4,5-b] pyridine

3- [3-bromo-2- (2-ethoxycarbonylphenyl) obtained by performing Example 19 twice with ethanol (1.2 mL), water (0.3 mL) and sodium hydroxide (34 mg, 0.840 mmol). ) -2H-indazol-5-yl] methyl-7-methyl-2-propyl-3H-imidazo [4,5-b] pyridine (0.149 mg, 0.280 mmol) and the mixture was stirred at room temperature for 15.5 hours. Stir while. After concentration, partition into water (2.5 mL) and ether (5 mL). The pH is adjusted to 5 by dropwise addition of concentrated hydrochloric acid to the aqueous layer. The resulting solid was filtered off, washed twice with water (1 mL) and dried overnight at 37 ° C. to 3- [3-bromo-2- (2-carboxyphenyl) -2H-indazol-5-yl] methyl 84 mg of -7-methyl-2-propyl-3H-imidazo [4,5-b] pyridine is obtained.

Reference Example 10

3-{[3-bromo-2- [2- (2-triphenylmethyl) -2H-tetrazol-5-yl) phenyl] -2H-indazol-5-yl] methyl} -2-ethyl- Synthesis of 5,7-dimethyl-3H-imidazo [4,5-b] pyridine

Sodium hydride (15 mg, 0.366 mmol) was added to a solution of 2-ethyl-5,7-dimethyl-1H-imidazo [4,5-b] pyridine (58 mg, 0.333 mmol) in DMF (2 mL) and 30 To the solution obtained by stirring for 5 minutes, 5- {2- [3-bromo-5- (bromomethyl) -2H-indazol-2-yl] phenyl} -2- (triphenyl) obtained in Reference Example 9 Methyl) -2H-tetrazole (0.250 g, 0.370 mmol) is added. The mixture is stirred at rt for 16 h. After concentration, it is partitioned into ethyl acetate (10 mL) and water (5 mL). The organic layer is dried over magnesium sulfate and filtered. The filtrate was concentrated and subjected to flash chromatography on silica gel using a mixed solvent of dichloromectin / methanol (100: 1) to obtain 3-{[3-bromo-2- [2- (2-triphenylmethyl ) -2H-tetrazol-5-yl) phenyl] -2H-indazol-5-yl] methyl} -2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridine 0.134 g To obtain.

Example 21

3-{[3-bromo-2- [2- (2-tetrazol-5-yl) phenyl] -2H-indazol-5-yl] methyl} -2-ethyl-5,7-dimethyl-3H Synthesis of -imidazo [4,5-b] pyridine

3-{[3-bromo-2- [2- (2-triphenylmethyl) -2H-tetrazol-5-yl) phenyl] -2H-indazol-5-yl] methyl obtained in Reference Example 10. } -2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridine (0.134 g) is dissolved in dichloromethane (2 mL) and formic acid (2 mL) is added thereto. The mixture is stirred at rt for 48 h and concentrated. The pH is adjusted to 12 by adding 1N sodium hydroxide aqueous solution thereto. The liquid portion is taken and washed with ether (10 mL) and dichloromethane (20 mL). Concentrated hydrochloric acid is added to the aqueous layer with stirring to adjust the pH to 7 and the aqueous layer is extracted with ethyl acetate (20 mL). The organic layer is dried over magnesium sulfate, filtered and concentrated. Acetone (1 mL) is added to the residue to dissolve and hexane (15 mL) is added. The resulting solid is filtered off, washed twice with hexane (2.5 mL) and dried in vacuo to be 3-{[3-bromo-2- [2- (1H-tetrazol-5-yl) phenyl] -2H-. Zol-5-yl] methyl} -2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridine is obtained 7.0 mg.

Reference Example 11

3-{[3-bromo-2- [2- (2-triphenylmethyl) -2H-tetrazol-5-yl) phenyl] -2H-indazol-5-yl] methyl} -7-methyl- Synthesis of 2-propyl-3H-imidazo [4,5-b] pyridine

7-methyl-2-propyl-3H-imidazo [4,5-b] pyridine (0.22g, 0.325mmol instead of 2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridine ), Followed by a similar method as in Reference Example 10, to obtain 3-{[3-bromo-2- [2- (2-triphenylmethyl) -2H-tetrazol-5-yl) phenyl] -2H. 82 mg of -indazol-5-yl] methyl} -7-methyl-2-propyl-3H-imidazo [4,5-b] pyridine is obtained.

Example 22

3-{[3-bromo-2- [2- (2-tetrazol-5-yl) phenyl] -2H-indazol-5-yl] methyl} -7-ethyl-2-propyl-3H-imide Synthesis of Multizo [4,5-b] pyridine

3-{[3-bromo-2- [2- (2-triphenylmethyl) -2H-tetrazol-5-yl) phenyl] -2H-indazol-5-yl] methyl obtained in Reference Example 11 } -7-methyl-2-propyl-3H-imidazo [4,5-b] pyridine (82 mg) was treated in the same manner as in Example 21 to give 3-{[3-bromo-2- [ 10 mg of 2- (1H-tetrazol-5-yl) phenyl] -2H-indazol-5-yl] methyl} -7-methyl-2-propyl-3H-imidazo [4,5-b] pyridine To obtain.

Reference Example 12

3-{[3-bromo-2- [2- (2-triphenylmethyl) -2H-tetrazol-5-yl) phenyl] -2H-indazol-5-yl] methyl} -2-methyl- Synthesis of 3H-imidazo [4,5-b] pyridine

2-butyl-1H-imidazo [4,5-b] pyridine (0.22 g, 0.325 mmol) instead of 2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridine A method similar to that in Reference Example 10 was conducted to obtain 3-{[3-bromo-2- [2- (2-triphenylmethyl) -2H-tetrazol-5-yl) phenyl] -2H-indazole- 75 mg of 5-yl] methyl} -2-methyl-3H-imidazo [4,5-b] pyridine is obtained.

Example 23

3-{[3-bromo-2- [2- (1H-tetrazol-5-yl) phenyl] -2H-indazol-5-yl] methyl} -2-propyl-3H-imidazo [4, 5-b] Synthesis of Pyridine

3-{[3-bromo-2- [2- (2-triphenylmethyl) -2H-tetrazol-5-yl) phenyl] -2H-indazol-5-yl] methyl obtained in Reference Example 12 } -2-butyl-3H-imidazo [4,5-b] pyridine (75 mg) was treated in the same manner as in Example 21 to give 3-{[3-bromo-2- [2- (1 9 mg of H-tetrazol-5-yl) phenyl] -2H-indazol-5-yl] methyl} -2-butyl-3H-imidazo [4,5-b] pyridine are obtained.

Reference Example 13

Synthesis of 5- [2- (3-chloro-5-methyl-2H-indazol-2-yl) phenyl] -2- (triphenylmethyl) -2H-tetrazole

5- [2- (5-methyl-2H-indazol-2-yl) phenyl] -2- (triphenylmethyl) -2H-tetrazole obtained in Reference Example 8 was used instead of N-bromosuccinimide. To N-chlorosuccinimide (1 equivalent), the same treatment as in Reference Example 4 was carried out to give 5- [2- (3-chloro-5-methyl-2H-indazol-2-yl) phenyl] -2- (triphenylmethyl) -2H-tetrazole is obtained.

Reference Example 14

3-{[3-chloro-2- [2- (2- (triphenylmethyl) -2H-tetrazol-5-yl) phenyl] -2H-indazol-5-yl] methyl} -2-ethyl- Synthesis of 5,7-dimethyl-3H-imidazo [4,5-b] pyridine

5- [2- (3-bromo-5-methyl-2H-indazol-2-yl) phenyl] -2- (triphenylmethyl) -2H-tetrazole instead of 5- [ 3-{[in a similar manner as in Example 17 using 2- (3-chloro-5-methyl-2H-indazol-2-yl) phenyl] -2- (triphenylmethyl) -2H-tetrazole 3-chloro-2- [2- (2-triphenylmethyl) -2H-tetrazol-5-yl) phenyl] -2H-indazol-5-yl] methyl} -2-ethyl-5,7-dimethyl 0.492 g of -3H-imidazo [4,5-b] pyridine is obtained.

Example 24

3-{[3-chloro-2- [2- (1H-tetrazol-5-yl) phenyl] -2H-indazol-5-yl] methyl} -2-ethyl-5,7-dimethyl-3H- Synthesis of Imidazo [4,5-b] pyridine

3-{[3-chloro-2- [2- (2- (triphenylmethyl-2H-tetrazol-5-yl) fetyl] -2H-indazol-5-yl] methyl} obtained in Reference Example 14. Methanol (5.5 mL) is added to 2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridine (0.492 g) and the mixture is stirred, with concentrated hydrochloric acid (5.5 mL). The mixture is then added dropwise under ice cooling, and the mixture is stirred at room temperature for 19 hours, an aqueous 10N sodium hydroxide solution is added under ice cooling to adjust the pH to 13, and then ion-exchanged water (10 ml) is added. The cake is washed with 1N aqueous sodium hydroxide solution (10 mL), with stirring to add the concentrated hydrochloric acid to the filtrate to adjust the pH to 5. The filtrate is extracted with ethyl acetate (55 mL) The organic layer is dried over magnesium sulfate and The residue is dissolved in ethyl acetate (1 mL) and hexane (15 mL) is added with stirring The resulting solid is filtered off and hexane (5 mL). Washed twice and vacuum dried

3-{[3-chloro-2- [2- (1H-tetrazol-5-yl) phenyl] -2H-indazol-5-yl] methyl} -2-ethyl-5,7-dimethyl-3H- 43 mg of imidazo [4,5-b] pyridine is obtained.

Reference Example 15

Synthesis of 3-chloro-2- (5-methyl-2H-indazol-2-yl) benzonitrile.

Toluene (66 ml) is added to 5-methyl-2-nitrobenzaldehyde (10.9 g, 66.0 mmol) obtained in Reference Example 1, and the mixture is stirred. 2-amino-6-chlorobenzonitrile (10.1 g, 66.0 mmol) is added there. After refluxing for 1 day under stirring, 5A (66 g) of molecular sieve is added thereto and the mixture is left overnight. The mixture is filtered and the cake is washed six times with chloroform (70 mL). The wash is concentrated and suspended in hexane (70 mL). The resulting solid is filtered off, washed with hexane (70 mL) and hexane (35 mL) and dried in vacuo. Triethyl phosphite (36.5 mL, 212.7 mmol) was added to the residue, and the mixture was refluxed for 1 hour and then cooled. The resulting solid is filtered off, washed four times with methanol (30 mL) and dried in vacuo to yield 4.87 g of 3-chloro-2- (5-methyl-2H-indazol-2-yl) benzonitrile. Further secondary crystals (0.19 g) are obtained from the wash liquor.

Reference Example 16

Synthesis of 5- [3-chloro-2- (5-methyl-2H-indazol-2-yl) phenyl] -2- (triphenylmethyl) -2H-tetrazole

3-chloro-2- (5-methyl-2H-indazol-2-yl) benzonitrile (5.06) obtained in Reference Example 15 instead of 2- (5-methyl-2H-indazol-2-yl) benzonitrile a method similar to that in Reference Example 8 was carried out using g) to obtain 5- [3-chloro-2- (5-methyl-2H-indazol-2-yl) phenyl] -2- (triphenylmethyl) -2H 8.71 g of tetrazole is obtained.

Reference Example 17

3-{[3-bromo-2- [3-chloro-2- (2- (triphenylmethyl) -2H-tetrazol-5-yl) phenyl] -2H-indazol-5-yl] methyl} Synthesis of 2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridine

5- [3-chloro-2- (5-methyl-2H-indazol-2-yl) phenyl] -2- (triphenylmethyl) -2H-tetrazole obtained with carbon tetrachloride (40 ml) obtained in Reference Example 16. (4.0 g, 7.23 mmol), and the mixture is stirred. N-bromosuccinimide (1.42 g, 7.96 mmol) is added thereto and the mixture is heated to reflux for 1 hour. N-bromosuccinimide (1.22 g, 6.89 mmol) and azobisisobutyronitrile (57 mg, 0.345 mmol) were added thereto, and the mixture was heated to reflux for 2.5 hours. After cooling, the mixture is diluted with dichloromethane (40 mL) and poured into water (40 mL). The organic layer is dried over magnesium sulfate, filtered and concentrated. The residue is dried in vacuo. The residue obtained as above was added with sodium hydride (0.257 g, 5.88 mmol) in different reaction vessels in 2-ethyl-5,7-dimethyl-1H-imidazo in DMF (39 mL) [4,5- b] to pyridine (1.03 g, 5.88 mmol) solution and to the solution obtained by stirring for 30 minutes. The mixture is stirred at rt for 15 h, concentrated and partitioned between ethyl acetate (100 mL) and water (100 mL). The aqueous layer is extracted with ethyl acetate (100 mL) and then with dichloromethane (100 mL). The organic layer is dried over magnesium sulfate and filtered. The filtrate was concentrated and flash chromatographed on silica gel using a mixed solvent of hexane / ethyl acetate (2: 3) to give 3-{[3-bromo-2- [3-chloro-2- (2- ( Triphenylmethyl) -2H-tetrazol-5-yl) phenyl] -2H-indazol-5-yl] methyl} -2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] 0.992 g of pyridine is obtained.

Example 25

3-{[3-bromo-2- [3-chloro-2- (1H-tetrazol-5-yl) phenyl] -2H-indazol-5-yl] methyl} -2-ethyl-5,7 Synthesis of -dimethyl-3H-imidazo [4,5-b] pyridine

3-{[3-bromo-2- [3-chloro-2- (2- (triphenylmethyl) -2H-tetrazol-5-yl) phenyl] -2H-indazole- obtained in Reference Example 17. 5-yl] methyl} -2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridine (0.800 g, 0.994 mmol) was treated in the same manner as in Example 24 to obtain 3- { [3-bromo-2- [3-chloro-2- (1H-tetrazol-5-yl) phenyl] -2H-indazol-5-yl] methyl} -2-ethyl-5,7-dimethyl- 0.324 g of 3H-imidazo [4,5-b] pyridine is obtained.

In a similar manner, the following compounds can be obtained.

Experimental Example 1

Inhibitory experiment of angiotensin II on rat smooth muscle cells.

Compound ¹²⁵ I-Tyr ⁴ -Angiotensin II of the present invention (0.25 μCi, 150 μl, NEX-105, NEX-105, abbreviated ¹²⁵ I-AII below) was added to smooth muscle cells derived from rat aorta so that the mixture was allowed to stand at room temperature 1 Incubate for hours. Unbound ¹²⁵ I-AII was washed with PBS (phosphate buffer), and the radioactivity of bound ¹²⁵ I-AII was measured, from which angiotensin II to the receptor of each compound of the present invention prepared in each Example was prepared. Inhibitory activity (IC ₅₀ ) is measured. The results are as follows.

IC ₅₀ of the compound of Example 4: 4.3 × 10 ⁻⁹ M

IC ₅₀ of the compound of Example 5: 4.0 × 10 ⁻⁸ M

IC ₅₀ of the compound of Example 6: 1.9 × 10 ⁻⁸ M

IC ₅₀ of the compound of Example 7: 1.3 × 10 ⁻⁷ M

IC ₅₀ of the compound of Example 9: 2.5 × 10 ⁻⁹ M

IC ₅₀ of the compound of Example 10: 7.2 × 10 ⁻⁷ M

IC ₅₀ of the compound of Example 12: 6.0 × 10 ⁻⁸ M

IC ₅₀ of the compound of Example 14: 2.5 × 10 ^-9 M

IC ₅₀ of the compound of Example 16: 6.7 × 10 ^-9 M

IC ₅₀ of the compound of Example 18: 2.0 × 10 ⁻⁹ M

IC ₅₀ of the compound of Example 20: 1.4 × 10 ⁻⁹ M

IC ₅₀ of the compound of Example 21: 1.1 × 10 ⁻⁹ M

IC ₅₀ of the compound of Example 22: 1.8 × 10 ⁻⁹ M

IC ₅₀ of the compound of Example 23: 3.1 × 10 ⁻⁹ M

IC ₅₀ of the compound of Example 24: 8.0 × 10 ⁻¹⁰ M

IC ₅₀ of the compound of Example 25: 7.2 × 10 ⁻¹⁰ M

[Example 1]

refine

(1), (3) and (4) are previously passed through a 100-mesh sieve. (1), (3), (4) and (2) are each dried until a constant moisture content is reached and mixed using a mixer at the above-described weight ratio. Next, (5) is added to the homogeneous mixed powder, mixed for a short time (30 seconds), and the mixed powder is compressed into tablets (pounds: 6.3 mm?, 6.0 mm R) having 85 mg per tablet.

The tablets obtained can be coated with a gastric film coating or an edible colorant, such as poly (vinyl acetal) diethylaminoacetate, which is commonly used as needed.

[Example 2]

Capsule

The ingredients are weighed and mixed homogeneously. The mixed powder is filled with 200 mg of hard gelatin capsules.

[Example 3]

Injection

The mixed solution of the above components is filtered with a membrane filter paper, followed by further sterilization filtration. Next, the filtrate is aseptically dispensed into the vial, filled with nitrogen gas, and the vial is sealed to obtain an intravenous injection.

Toxicity test results: Acute toxicity test

Male mice (group 1: 5) 7 weeks old were orally administered with the compound of Example 18 to obtain LD ₅₀ values. As a result, LD ₅₀ value was 500 ml / kg.

Claims (12)

Isoindazole compounds of the following general formula (1) or salts thereof: [Wherein Q is a heterocyclic derivative of the following general formula (2) or (3); [In the formulas (1), (2) and (3), R ¹ is a lower alkyl group or alkoxy; R ² and R ³ may be the same or different and each independently represent a hydrogen atom, a halogen atom, a lower alkyl group,-(CH ₂ ) _n R ⁹ , or-(CH ₂ ) _p COR ¹⁰ ; R ⁴ and R ⁵ may be the same or different and each independently represent a hydrogen atom or a halogen atom; R ⁶ is a carboxyl group, -COOR ¹¹ or a C-linked tetrazolyl group; R ⁷ and R ⁸ may be the same or different and each independently represent a hydrogen atom or a halogen atom; X and Y may be the same or different and each is independently CH or a nitrogen atom; In the above definition, R ⁹ is a hydroxyl group; R ¹⁰ is a hydrogen atom, a hydroxyl group or an alkoxy, and R ¹¹ is a lower alkyl group; m: integer of 1-6; n: an integer of 1 to 4; p is an integer of 0 to 4] The compound according to claim 1, wherein in formula (1), Q is a heterocyclic derivative of formula (2) or (3), wherein R ¹ is a lower alkyl group; R ² and R ³ may be the same or different and each independently represent a hydrogen atom, a halogen atom, a lower alkyl group,-(CH ₂ ) _n R ⁹ , or-(CH ₂ ) _p COR ¹⁰ , wherein R ⁹ is An isoindazole compound or a salt thereof, wherein the compound is a hydroxyl group, R ¹⁰ is a hydrogen atom, a hydroxyl group or an alkoxyl group, n is an integer of 1 to 4 and P is an integer of 0 to 4). The isoindazole compound or a salt thereof according to claim 1 or 2, wherein in formula (1), R ⁴ is a hydrogen atom and R ⁵ is a hydrogen atom or a halogen atom. The isoindazole compound or a salt thereof according to claim 1 or 2, wherein in formula (1), R ⁶ is a carboxyl group or a C-linked tetrazolyl group. The isoindazole compound or a salt thereof according to claim 1 or 2, wherein in Formula (1), R ⁷ and R ⁸ may be the same or different and each is independently a hydrogen atom or a chlorine atom. The compound of claim 1, wherein in formula (1), Q is a heterocyclic derivative of formula (2), wherein R ¹ is a lower alkyl group, R ² is a chlorine atom, and R ³ is-(CH ₂ ) _n R ⁹ or-(CH ₂ ) _p COR ¹⁰ (wherein R ⁹ is a hydroxyl group, R ¹⁰ is a hydrogen atom, a hydroxyl group or an alkoxyl group, n is an integer from 1 to 4 and P is from 0 to 4 Is an integer) or a salt thereof. The compound of claim 1, wherein in formula (1), Q is a heterocyclic derivative of formula (2), wherein R is^OneThis is a lower alkyl group, R²Is a chlorine atom, R³Is-(CH₂)_nR⁹, Or-(CH₂)_pCOR 10 (where R⁹Is a hydroxyl group, R¹⁰Is a hydrogen atom, a hydroxyl group or an alkoxyl group, n is 1 and P is 0 or 1), R⁴Is a hydrogen atom, R⁵Is a hydrogen atom, a chlorine atom or a bromine atom, and R⁶Is a carboxyl group or a C-linked tetrazolyl group and R⁷And R⁸These may be the same or different and each independently is an isoindazole compound or a salt thereof. The isoindazole compound or a salt thereof according to claim 1 or 2, wherein in formula (1), Q is a heterocyclic derivative of formula (3), wherein X is a nitrogen atom and Y is CH. The compound of claim 1, wherein in formula (1), Q is a heterocyclic derivative of formula (3), wherein R ¹ is a lower alkyl group, and R ² and R ³ may be the same or different and each independently represent a hydrogen atom. Or a lower alkyl group, X is a nitrogen atom, Y is CH, R ⁴ is a hydrogen atom, R ⁵ is a hydrogen atom, a chlorine atom or a bromine atom, R ⁶ is a carboxyl group or a C-bonded tetrazolyl group, R Isoindazole compounds or salts thereof, wherein ⁷ and R ⁸ may be the same or different and each independently represent a hydrogen atom or a chlorine atom. The compound of claim 1, wherein 1- [3-bromo-2- (2-carboxyphenyl) -2H-indazol-5-yl] methyl-2-butyl-4-chloro-5- (hydroxymethyl)- 1H-imidazole, 1-{[3-bromo-2- [2- (1H-tetrazol-5-yl) phenyl] -2H-indazol-5-yl] methyl} -2-butyl-4- Chloro-5- (hydroxymethyl) -1H-imidazole, 2-butyl-3- [3-bromo-2- (2-carboxyphenyl) -2H-indazol-5-yl] methyl-3H-imi Dazole [4,5-b] pyridine sodium salt, 3- [3-bromo-2- (2-carboxyphenyl) -2H-indazol-5-yl] methyl-5,7-dimethyl-2-ethyl- 3H-imidazo [4,5-b] pyridine sodium, 3-{[3-bromo-2- [2- (1H-tetrazol-5-yl) phenyl] -2H-indazol-5-yl] Methyl} -2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridine and 3-{[3-bromo-2- [2- (1H-tetrazol-5-yl) Isoindazole compounds selected from the group consisting of phenyl] -2H-indazol-5-yl] methyl} -2-butyl-3H-imidazo [4,5-b] pyridine or salts thereof. A method for producing the isoindazole compound or salt thereof according to claim 1, wherein the compound of formula (4) is reacted with a compound of formula (5) or (6); [Wherein L is a leaving group and R ²⁴ , R ²⁵ , R ²⁶ , R ²⁷ and R ²⁸ are the same as the corresponding R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ of General Formula (1), respectively; , Which can be converted to the corresponding R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ , respectively] [Wherein, R ²³ , R ²² and R ²³ are the same as the corresponding R ¹ , R ² and R ³ of the general formula (2), or can be converted into the corresponding R ¹ , R ² and R ³ , respectively to be] [Wherein R ²¹ , R ²² and R ²³ are each the same as corresponding R ¹ , R ² and R ^{3 in} formula (3), or can be converted to the corresponding R ¹ , R ² and R ³ , respectively Is a flag] An angiotensin II antagonist comprising the isoindazole compound of claim 1 or a salt thereof and a pharmaceutically acceptable carrier.